Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function. Deleterious angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al., 1995, Trends Pharmacol. Sci. 16:57-66; Folknan, 1995, Nature Medicine 1:27-31). Vascular endothelial growth factors (VEGFs) are regulators of angiogenesis. VEGF binds to tyrosine kinase receptors on the cell surface, known as VEGFR1 (Flt-1), VEGFR2 (Flk-1, KDR), and VEGFR3 (Flt-4). This results in stimulation of the receptor-associated tyrosine kinase activity, which leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signaling cascade leading to a variety of cellular responses including inducing endothelial cell proliferation, promoting cell migration, and inhibiting apoptosis.
U.S. Pat. No. RE42,353 discloses certain quinazoline compounds that inhibit the effects of VEGF. The quinazoline compounds are useful for treating diseases associated with angiogenesis and/or increased vascular permeability such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, and ocular diseases with retinal vessel proliferation. However, a wide variability in response to treatment with these drugs has been observed in cancer patients.
Michalski et al. developed radio-labeled VEGF/VEGFR antibodies for imaging VEGFR expression in various disease models (European J Nuclear Med Mol Imaging, 2011, 38:358-377). However, these probes exhibit low to moderate tumor-to-background ratio in VEGFR expressing cells, despite their high receptor affinity. The imaging potential of these probes are also limited by the slow clearance of antibodies from the blood, high uptake in non-targeted tissues such as kidney, and poor extravasations and diffusion into the extracellular space.
What are needed are compounds and methods to non-invasively determine VEGFR expression levels in cells in vivo. Further, compounds that bind selectively to VEGFR expressing cells are also needed. Still further, what are needed are compounds that exhibit fast clearance from the blood and/or exhibit low uptake in non-targeted tissues such as the kidney. The compositions and methods disclosed herein address these and other needs.